Where do people live in relation to rivers? Human societies evolved alongside rivers, but how are modern human societies related to rivers? We conducted a global analysis to assess the linkages between river geomorphologic structure and human settlement patterns. We found globally consistent patterns of preferential downstream clustering of human settlements. Across all six populated continents, human settlements are clustered near the outlets of major river basins, with settlement density decreasing exponentially with distance upstream. This downstream clustering suggests an optimum distribution of humans in large river basins for trade, transport and resource utilization. However, there are also attendant implications for human impacts on rivers. Recognition of such spatial patterns helps generalize management of river water quantity, quality, and biological.